Bactericidal/Permeability-Increasing Protein Inhibits Induction of Macrophage Nitric Oxide Production by Lipopolysaccharide

A recombinant (r) NH2-terminal fragment of bactericidal/permeability-increasing protein, rBPI23, was shown to inhibit murine macrophage nitric oxide (NO) production elicited by lipopolysaccharide (LPS) plus interferon-β (IFN-β). Normal mouse plasma amplified NO synthesis (measured as NO-2 release) at LPS concentrations of 1-10 ng/mL, and antibody to the plasma LPS-binding protein (LBP) partially inhibited N02 release in the presence of normal mouse plasma. rBPI23 (1 µg/mL) effectively inhibited LPS-dependent NO-2 release in the presence or absence of normal mouse plasma. Fifty percent inhibition of IFN-β/LPS-elicited NO-2 production or of binding of fluoresceinated LPS was obtained with ∼0.2 µg/mL rBPI23. These results provide a basis for studies of rBPI23 effects on NO synthase activity in murine models of gramnegative sepsi

Competition between Bactericidal/Permeability-Increasing Protein and Lipopolysaccharide-Binding Protein for Lipopolysaccharide Binding to Monocytes

The bactericidal/permeability-increasing protein (BPI) inhibits the lipopolysaccharide (LPS)mediated activation of monocytes. Due to its inhibitory activity for various LPS, BPI has therapeutic potential in endotoxic shock. To be efficient in vivo, BPI should overcome the action of LPS-binding protein (LBP), a serum molecule that increases the expression of LPS-inducible genes via CD 14 of monocytes. rBPI23, a recombinant fragment of BPI, prevented in a dose-dependent manner the binding and the internalization of LPS mediated by LBP. Consequently, rBPI23 also inhibited LPS-induced tumor necrosis factor (TNFα) synthesis from monocytes. LPS- and LBP-mediated activation of monocytes was totally inhibited when LPS was preincubated with rBPI23. Adding rBPI23 at the same time as LBP resulted in an important but partial inhibition of TNFα release, but this inhibition vanished with delaying the time of addition of rBPI23. These studies suggest that the inhibitory activity of BPI is related to its ability to compete with LBP for LP